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Human adenylate kinase 2 deficiency causes a profound hematopoietic defect associated with sensorineural deafness

Abstract

Reticular dysgenesis is an autosomal recessive form of human severe combined immunodeficiency characterized by an early differentiation arrest in the myeloid lineage and impaired lymphoid maturation. In addition, affected newborns have bilateral sensorineural deafness. Here we identify biallelic mutations in AK2 (adenylate kinase 2) in seven individuals affected with reticular dysgenesis. These mutations result in absent or strongly decreased protein expression. We then demonstrate that restoration of AK2 expression in the bone marrow cells of individuals with reticular dysgenesis overcomes the neutrophil differentiation arrest, underlining its specific requirement in the development of a restricted set of hematopoietic lineages. Last, we establish that AK2 is specifically expressed in the stria vascularis region of the inner ear, which provides an explanation of the sensorineural deafness in these individuals. These results identify a previously unknown mechanism involved in regulation of hematopoietic cell differentiation and in one of the most severe human immunodeficiency syndromes.

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Figure 1: AK2 gene mutations in seven individuals with reticular dysgenesis.
Figure 2: Gene and protein expression analysis of AK2 in cell lines derived from individuals with reticular dysgenesis.
Figure 3: Complementation of the neutrophil differentiation defect by restoration of AK2 expression.
Figure 4: AK2 distribution in the mouse inner ear.

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Acknowledgements

We wish to thank the Antoine Béclère Hospital and the Pitié-Salpetrière Hospital for providing cord blood samples, the French National Genotyping Centre for contributing to the genome-wide linkage scan and P. Cherukuri and the NISC Comparative Sequencing Program (NISC, National Human Genome Research Institute, National Institutes of Health) for their help in sequencing the region of interest. We are grateful to I. André-Schmutz, S. Blanche, J.L. Casanova, J. Chinen, C. Chomienne, L. Coulombel, L. dal Cortivo, F. Le Deist, G. de Saint-Basile and J.P. de Villartay for discussions and assistance, and to all staff nurses who cared for the patients. We also thank the subjects' families for their participation. We acknowledge C. Hue, C. Martinache, J. Rouiller, C. Soudais and M.C. Stolzenberg for their technical assistance, as well as D. Fraser for his language editing review. The study was funded by the French National Institute for Health and Medical Research (INSERM), the French Institute for Rare Diseases (GIS-Institut des maladies rares), the French National Research Agency (ANR) and the Intramural Research Program of the National Human Genome Research Institute (NIH).

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Contributions

C.L.-P. and E.M.S. contributed equally to this study by performing most of the experimental work and analysis, with the assistance of C.D.-d.C. and E.M. C. Picard and F.R.-L. performed apoptotic tests on the fibroblasts, gave critical advice and comments in designing the experiments. Experiments shown in Figure 4 were performed by V.M. A.D. performed the RNA interference experiments. F.V. provided expertise in histological examination. K.L.S.-S. mapped P6 deletion and found P7 mutation. J.C.M. performed the sequencing project. C.B. performed the genome-wide linkage scan. C. Picard, L.M.N., N.M.W., A. Ferster, M.M.A. and M.C.-C. recruited and diagnosed the individuals with reticular dysgenesis and provided materials from them. F. Calvo gave critical comments in designing the experiments and helped to sequence the healthy and pathological samples. C. Petit contributed to the design of the inner ear experiments and F. Candotti designed and coordinated the sequencing project. C. Picard and L.A. performed the lod-score analysis. L.A. and A. Fischer contributed equally to this study. M.C.-C. supervised the overall project. M.C.-C., C.L.-P., E.M.S., L.A. and A. Fischer wrote the paper and added the comments from all authors.

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Correspondence to Marina Cavazzana-Calvo.

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Lagresle-Peyrou, C., Six, E., Picard, C. et al. Human adenylate kinase 2 deficiency causes a profound hematopoietic defect associated with sensorineural deafness. Nat Genet 41, 106–111 (2009). https://doi.org/10.1038/ng.278

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